In summary, we report for the first time the association of PSPN gene with HSCR and confirm the involvement of NRTN in the disease, with the identification of novel variants in those genes.
Although mutations in eight different genes (EDNRB, EDN3, ECE1, SOX10, RET, GDNF, NTN, SIP1) have been identified in affected individuals, it is now clear that RET and EDNRB are the primary genes implicated in the etiology of HSCR.
Germline mutations of the RET proto-oncogene (RET), its ligand glial cell-derived neurotrophic factor (GDNF), and neurturin (NTN) gene have been reported in patients with Hirschsprung's disease.
Interestingly, it appears that the NTN mutation reported here is not sufficient to cause HSCR, and this multiplex family also segregates a RET mutation.